Successful treatments for most types of cancer are readily available in the form of surgical and chemotherapeutic techniques which dramatically increase survival for patients who receive accurate and timely diagnoses. Unfortunately, even though a physician may be able to predict whether a patient's tumor is "benign" or "malignant," the reliability and significance of this prediction is uncertain. Most commonly, a diagnosis of malignancy depends on histopathological findings, determined by microscopic analysis of biopsies or other tissue samples taken from the patient. Histopathologic diagnosis of cancer presents a number of major drawbacks, not the least important of which are that: i) using currently available techniques, histopathologic assessment of tumor malignancy often requires relatively extensive tissue sampling, so that in many cases low-morbidity sampling techniques such as needle biopsy cannot be applied in a clinically useful manner; ii) histopathologic markers for malignancy are typically assessed qualitatively, leaving a wide margin for error and discrepancy between individual pathologists in evaluating samples; and iii) histopathologic markers for malignancy vary widely between different forms of cancer, making a standard method of analysis impracticable. Because of this situation, individual histopathologists may require special training to expertly diagnose specific forms of cancer, or may be poorly qualified for diagnosing a wide range of cancers. For most forms of cancer, the term malignancy actually embraces a broad spectrum of disease states, or so-called "grades" of malignancy. Different schools of teaching may apply different grading systems to the same form of cancer, while grading systems for different forms of cancer may be entirely incomparable. These circumstances add further uncertainty to the qualitative histopathologic diagnosis of cancer.
Even if methods for predicting tumor malignancy were considerably easier, and less risky and prone to error, cancer diagnostic methods would remain critically flawed since it is still unclear how tumor malignancy relates to the ability of a tumor to metastasize, or spread from its site of origin. Although it is generally accepted that a "benign" tumor poses little or no threat of metastasis, and that tumors of low and high grade malignancy pose lesser or greater threats of metastasis, respectively, a reliable and direct correlation between the biologic potential to metastasize, and malignancy grade is conspicuously absent for all forms of cancer. This suggests that factors other than cellular differentiation are responsible for a tumor cell's ability to metastasize (see Kramer et al., Cancer 48: 271-273, 1981). These circumstances also imply that a significant percentage of intermediate grade malignancies actually possess unforeseeably low biologic potentials. Unfortunately, in such a case, the physician might be compelled to employ therapy such as surgery, radiation, or chemotherapy, even though such treatments may in fact decrease the patient's chances for survival or result in significant morbidity. Conversely, life-saving treatments may often be withheld from patients who present lower grade malignancies, which actually possess high potentials for metastasis. To provide more effective tools for cancer diagnosis, it is therefore necessary to develop technologies to determine the biologic potential of carcinomas directly. Such technologies call for discovery of relevant "markers" of biologic potential, and development of tools to evaluate and measure these markers. An optimal technology of this sort should be applicable with minimal risk and morbidity to a wide range of cancers, and be quantitative, reproducible, and require minimal expenditure of time and expertise.
Previous attempts to develop such diagnostic methods for determining the biologic potential of carcinomas began with studies comparing malignancy grade in primary tumors with the presence or absence of lymphatic metastases in patients (see for example, Paulson et al., J. Urology 123: 697-699, 1980, and Kramer et at., Cancer 48: 271-273, 1981). These efforts suggested only a rough correlation between malignancy grade and metastasis, and biologic potential appeared unrelated to malignancy grade in the most common, intermediate grade tumors. Further, these studies typically involved histopathological analyses of whole organs, or large tissue samples obtained by surgery.
From this discussion, it is evident that there is a need for clinically useful methods for estimating biologic potential of carcinomas in patients. The present invention fulfills this need and provides other related advantages.